Michael Horowitz Discipline of Medicine, University of Adelaide and

Endocrine and Metabolic Unit , Royal Adelaide Hospital, Adelaide, South Australia

Differential properties of GLP-receptor agonists: The role of gastric emptying

Dualities of interest

•  In the past 2 years Michael Horowitz has been a member of advisory boards and/or has acted as a Consultant for Sanofi-Aventis, Merck Sharpe and Dohme, Boehringer-Ingelheim, Novartis, Astra Zeneca/BMS and Satiogen, and has received honoraria for these activities.

GLB.DIA.14.04.84

‘Diabetes is a disease of the stomach’

Arataeus of Cappuducia (~AD80)

Monnier et al, Diabetes Care (2009)

Breakfast Lunch Dinner 0.00 4.00

Postprandial Postabsorptive Fasting

Duration of the postprandial, postabsorptive, and fasting states

Role of the gut in glycaemic control

GIP CCK

GLP-1 PYY

nutrient

satiation

insulin secretion

slow gastric emptying

Overview •  measurement of gastric emptying •  prevalence and determinants of

disordered gastric emptying and gastrointestinal symptoms in diabetes-impact of glycaemia

•  effects of gastric emptying on glycaemia •  effects of endogenous and exogenous

GLP-1 on gastric emptying •  effects of GLP-1 agonists on gastric

emptying-relationship to glycaemia

Trituration Solid ‘Liquid’

Small intestine

Liquid

Emptying forces and

controls

Stomach

Chyme

20 s

50 ml.s-1

20 mlDuodenal outflow

Tran sp ylori c flow

Transpyloric flow

Malbert et al, J Physiol (1989)

Control of gastric emptying

+ _ •

•  Myogenic •  Neural •  Humoral

Small intestinal receptors

Pacemaker

Measurement of gastric emptying before ethics committees

The Holy Roman Emperor, Frederick II (1193-1250) ordered two men to be fed a large meal and then sent one hunting and ordered the other to rest to determine under which condition ‘digestion’ is aided. Frederick had both men executed and disemboweled to discover that the stomach of the man who had rested was empty, while that of the man who had been hunting was full.

‘Under circumstances characterised by���hostility and resentment, we observed in ���Tom, and in other subjects, engorgement of���the gastric mucosa and enhanced contractile ���activity in the stomach’

Dr Stewart Wolf with longtime patient, Tom Little, at the Oklahoma Medical Research Foundation in 1956

Wolf S, Wolff SG, Human gastric function, New York; Oxford University Press (1943)

‘We need to learn to measure what we value, not value what we can easily measure’

(Marcus Aurelius AD 121-180)

Methods to assess gastric motor function

•  scintigraphy •  stable isotope breath tests •  ultrasound •  Smart Pill® •  SPECT •  MRI •  absorption kinetics of oral drugs eg. paracetamol •  radiology (barium studies / radiopaque markers) •  intubation/aspiration

Gastric emptying

Manometry Electrogastrography

Gastric emptying in longstanding type 1 and type 2 diabetes

Horowitz et al, Eur J Nucl Med (1991)

0

20

40

60

80

100

0

10

20

30

40

50

60

70

P<0.001 P<0.02

Controls n = 25

Controls n =25

Diabetics n = 87

Diabetics n = 87

T50 (min)

Retention at 100 min (%)

Solid (100g minced beef)

Liquid (150ml 10% dextrose)

Solid gastric emptying measured with a carbon breath test in outpatients with type 1 and 2

diabetes (n=186)

Samsom et al, Diabetes Care (2003)

0

50

100

150

200

250

healthy volunteers

diabetic patients

T50 (min)

P<0.001

Chang et al, Diabetes Care (2012)

A 25 year (1985 – 2010) longitudinal evaluation of gastric emptying in diabetes (n=13)

r= 0.56, P<0.05 r= 0.82, P<0.01

Solid (100g minced beef)

Liquid (150mL 10% dextrose)

80

100

60

40

20

0 20 0 40 60 80 100

80

60

40

20

0 10 0 20 30 40 50

(% r

eten

tion

at 1

00 m

in)

T50

(min

)

Pathogenesis of disordered gastric emptying���in diabetes

extrinsic nerves enteric nerves Interstitial cells of Cajal smooth muscle immune cells

‘fixed’ pathological process reversible dysfunction induced by acute glycaemia

‘iv glucose suppresses gastric “hunger” contractions’

Stunkard and Wolff, J Clin Invest (1956)

0

2

4

6

8

10

0

2

4

6

8

10

Effect of hyperglycaemia (~15mmol/L) on gastric emptying in type 1 diabetes

Fraser et al, Diabetologia (1990)

Solid (100g ground beef)

Retention at 100 min

Liquid (150mL 10% dextrose)

50% emptying time

Euglycaemia Euglycaemia Hyperglycaemia Hyperglycaemia

Number of patients

with delayed gastric

emptying

Effect of acute hypoglycaemia (2.6 mmol/L) on gastric emptying in type 1 diabetes (n=20)

Retention (%)

Time (min)

Solid (100g minced beef)

Liquid (150ml water)

0

20

40

60

80

100

0 15 30 45 60 75 90 105 120 0

20

40

60

80

100

0 15 30 45 60 75 90 105 120

Euglycaemia Hypoglycaemia

* *

* *

*

*

* *

* * * # #

# P<0.05 * P<0.01

Russo et al, J Clin Endocrinol Metab (2005)

0

20

40

60

80

100

1 2 3

Effect of improved glycaemic control (~3 months) on gastric emptying in recently detected type 2 diabetes (n=30)

Laway et al, J Diabetes Complications (2013)

Gas

tric

em

ptyi

ng a

t 240

min

(%)

Healthy Controls

n = 20

HbA1c 4.5 ± 0.1%

Diabetes – Euglycaemia

n = 30

HbA1c 5.0 ± 0.1%

Diabetes – Hyperglycaemia

n = 30

HbA1c 10.5 ± 0.2%

P<0.001

Prevalence of upper gastrointestinal symptoms in type 1 diabetes

loss of appetite early satiation postprandial fullness nausea abdominal distension vomiting

Diabetic patients (%) 16.3 26.8 18.6 22.7 42.3 12.2

Control subjects (%) 3.6 6.1 8.5 9.1 24.4 3.0

P-value

<0.001 <0.001 <0.05 <0.01 <0.01 <0.01

Schvarcz et al, Diabet Med (1996)

0

2

4

6

8

1 0

1 2

1 4

1 6

0 2 0 4 0 6 0 8 0 1 0 0 1 2 0

r=0.32, P<0.005 Number of upper

gastrointestinal symptoms

Jones et al, J Nucl Med (1995)

Relationship between upper gastrointestinal symptoms and gastric emptying of solid in

longstanding type 1 and type 2 diabetes

Solid retention at 100 min (%)

Upper gastrointestinal symptoms in diabetes

•  occur frequently •  affect quality of life adversely •  pathogenesis poorly defined

-  disordered motor/sensory function -  gastric dysrhythmias - glycaemic control - autonomic/enteric neuropathy - psychiatric comorbidity

•  gastric emptying should be measured using scintigraphy or a breath test

•  there is a large inter- (1-4 kcal/min), but smaller intra-individual, variation in gastric emptying

•  gastric emptying is delayed in 30 - 50% of patients with long-standing type 1 or 2 diabetes (usually modestly) and is occasionally abnormally rapid

•  the pathogenesis of gastroparesis is heterogeneous •  gastric emptying is slower during acute hyperglycaemia

and accelerated by insulin-induced hypoglycaemia •  improved glycaemic control may normalise gastric

emptying •  the relationship of upper gastrointestinal symptoms with

the rate of gastric emptying is weak

Relationship between glycaemic response and ���gastric emptying (75g glucose) in normal subjects

Horowitz et al, Diabetologia (1993)

r = 0.65, p <0.01

% emptied at 30 min

AUC glucose 0-30 min

403020100140

160

180

200

220

240

260

n = 16

r = 0.60 p < 0.01

AUC glucose 0-60 min

% emptied at 60 min

3 0 0

4 0 0

5 0 0

6 0 0

7 0 0

8 0 0

9 0 0

1 0 0 0

0 1 0 2 0 3 0 4 0 5 0 6 0

Relationship between glycaemic response and gastric emptying (75g glucose) in type 2 diabetes

Jones et al, J Nucl Med (1996)

Gonlachanvit et al, Dig Dis Sci (2003)

150

200

250

300

350

100

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0 120 180 240 300 60

* *

*

*

* * *

** ●

0 120 60 180 240 300

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100

0

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0 120 60 180 240 300 0

20

40

60

80

100 ●

* *

* * * * * *

** ** ** ** **

** **

** **

Effects of erythromycin (200 mg iv) and morphine (8 mg iv) on solid and liquid gastric emptying and

blood glucose in type 2 diabetes (n=9)

Retention (%)

Retention (%)

mg/dl

Solid GE Liquid GE Blood glucose Placebo Erythromycin Morphine

Time (min)

* P < 0.05 vs Placebo ** P < 0.01 vs Placebo

•  gastric emptying is a major determinant of postprandial glycaemia in health and type 2 diabetes

•  slowing gastric emptying decreases postprandial glycaemic excursions in health and (non insulin-treated) type 2 diabetes

Relationship between alcohol absorption ���and gastric emptying

AU

C b

lood

alc

ohol

(mg

100m

l-1 m

in)

Liquid emptying at 60 min (%)

Horowitz et al, Am J Physiol (1989)

Liquid immediately after solid Liquid alone Liquid 90 min after solid

The confounder- GLP-1 slows ���gastric emptying

4

6

8

10

12

0 30 60 90 120 150 1800

20

40

60

80

100

0 30 60 90 120 150 180

Effects of exendin(9-39) on gastric emptying and glycaemia in healthy subjects (n = 10)

Ret

entio

n (%

)

Time (min)

P = 0.03

mm

ol/l

Exendin Placebo

4

6

8

10

12

-30 0 30 60 90 120150 180

BSL PLAC

BSL EX

Gastric emptying Blood glucose

P < 0.005

Deane et al, J Clin Endocrinol Metab (2010)

4

6

8

10

12

-30 0 30 60 90 120150 180

BSL PLAC

BSL EX

Effect of exogenous GLP-1 on gastric emptying in healthy young subjects (n = 10)

* #

* # *

# * # *

# * # *

# * 100

75

50

25

0 0 15 30 45 60 75 105 90 120 0 15 30 45 60 75 105 90 120

Retention (%)

* * * * * *

#

Time (min)

Solid (100 g minced beef)

Liquid (150 ml 10 % dextrose)

Saline GLP-1 [0.3] GLP-1 [0.9]

* GLP-1 [0.3] and [0.9] vs. control: P < 0.05 # GLP-1 [0.3] vs. GLP-1 [0.9]: P < 0.05

100

75

50

25

0

Little et al, J Clin Endocrinol Metab (2006)

*

# *

* *

*

*

-45 105 90 75 60 45 30 15 0 -15 -30 120 Time (min)

4

5

6

7

8

mmol/l

90 60 30 0 -30 120 10 20 30 40 50 60 70

mU/l # *

*

Blood glucose Plasma insulin

Effect of exogenous GLP-1 on blood glucose and plasma insulin in healthy young subjects (n = 10)

* GLP-1 [0.3] and [0.9] vs. control: P < 0.05 # GLP-1 [0.3] vs. GLP-1 [0.9]: P < 0.05

Saline GLP-1 [0.3] GLP-1 [0.9]

Little et al, J Clin Endocrinol Metab (2006)

GLP-1 slows gastric emptying in the critically ill* when emptying is‘normal’but not when it is delayed

Deane et al, Crit Care Med (2010)

‘normal’ gastric

emptying (n=14)

*

delayed gastric

emptying (n=11)

Gastric emptying coefficient

*P < 0.01

More rapid emptying

Slower emptying

*Non-diabetic patients admitted to intensive care, mechanically ventilated

Hypo – GLP-1

Hypo – Placebo Retention

(%)

Time (min)

GLP-1(1.2 pmol/kg/min iv) attenuates the acceleration of gastric emptying by hypoglycaemia

in healthy subjects (n=10)

Eu – GLP-1 Hypo – GLP-1

Hypo – Placebo Eu - Placebo

BGL 2.6 mmol/L

Plummer et al, Diabetes Care (2014)

There is tachyphylaxis to the effect of GLP-1 on gastric emptying with

sustained exposure

Placebo Acute GLP-1 Intermittent GLP-1

Scintigraphy Scintigraphy

-30 min 4 hours 23.5 hours 28 hours

GLP-1 Placebo

Scintigraphy

-30 min 4 hours 23.5 hours 28 hours Prolonged

GLP-1

Regimen A

Regimen B

642 kcal meal

642 kcal meal

642 kcal meal

Scintigraphy

642 kcal meal

Protocol

Umapathysivam et al, Diabetes (2013)

0

10

20

30

40

50

60

70

80

90

100

0 30 60 90 120 150 180 210 240

Intragastric retention

(%)

Time (min) 642 kcal

meal

Effects of prolonged and intermittent GLP-1 (0.8pmol/kg/min iv) on gastric emptying in healthy males (n=10)

Umapathysivam et al, Diabetes (2013)

Acute GLP-1 Intermittent GLP-1 Prolonged GLP-1 Saline

0

50

100

150

200

250

300

350

400

Placebo Acute Prolonged Intermittent

Post

pran

dial

gly

caem

ia

(mm

ol/L

.60)

Effects of prolonged and intermittent GLP-1 (0.8pmol/kg/min iv) on postprandial glycaemia (AUC0-60) in healthy males (n=10)

*

#P=0.007

Umapathysivam et al, Diabetes (2013)

*P=0.001

•  endogenous GLP-1 slows gastric emptying and thereby glucose absorption

•  inhibition of gastric emptying by acute administration of exogenous GLP-1 outweighs its insulinotropic effects

•  the reduction in postprandial glycaemia by exogenous

GLP-1 is related to slowing of gastric emptying and greater when gastric emptying is relatively more rapid

•  exogenous GLP-1 attenuates the acceleration of gastric emptying by hypoglycaemia

•  there is tachyphylaxis to the slowing of gastric

emptying by exogenous GLP-1 with sustained exposure

Currently available GLP-1 receptor agonists and compounds in late stage development

Product Generic name Company Dosing Phase

Byetta Exenatide Amylin/Lilly Twice daily Marketed

Victoza Liraglutide Novo Nordisk Once daily Marketed

Bydureon Exenatide-LAR Amylin/Lilly Once weekly Marketed

Lyxumia Lixisenatide Zealand Pharma/Sanofi-Aventis Once daily Marketed

Eperzan Albiglutide GlaxoSmithKline Once weekly EU and US

approval In Q1-2014

LY2189265 Dulaglutide Eli Lilly Once weekly Phase III

NN9535 Semaglutide Novo Nordisk Once weekly Phase II

GLP-1 receptor agonists exhibit differences in their effects on pre- and postprandial glucose • short-acting-‘prandial’ • long-acting-‘non-prandial’

Differentiation of GLP-1 RAs

Parameters Short-acting prandial Long-acting Compounds Exenatide, Lixisenatide Albiglutide, Dulaglutide,

Exenatide-LAR, Liraglutide

Half-life 2-5h 12h-several days

Effects Gastric emptying Marked slowing Minimal effect Fasting blood glucose Modest reduction Marked reduction Post-prandial glucose Marked reduction Modest reduction Fasting insulin Modest stimulation Marked stimulation Post-prandial insulin Reduction Modest stimulation

Glucagon Reduction Reduction

Adapted from Meier et al, Nat Rev Endocrinol (2012)

10µg exenatide 5µg exenatide Placebo

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10 11 12

Residual Activity

(%)

Time (h)

Exenatide bd dose-dependently slows solid gastric emptying in type 2 diabetes (n = 16)

Linnebjerg et al, Regul Pept (2008)

0

1

2

3

4

5

6

30 40 50 60 70 80 90 100 110 120

The magnitude of the effect of exenatide (10µg sc bd) on gastric emptying in type 2 diabetes is dependent on the

rate of gastric emptying on placebo

Rat

io T

50 (1

0µg

exen

atid

e/pl

aceb

o)

Placebo T50 (min)

r= -0.51, P<0.05

Linnebjerg et al, Regul Pept (2008)

Linnebjerg et al, Regul Pept (2008)

Effects of exenatide LAR and exenatide bd on paracetamol absorption in type 2 diabetes (n=51)

AUC (µg min/mL)

Exenatide once a week (LAR) Exenatide bd

Time (min) Time (min) 50 100 150 200 250 300 50 100 150 200 250 300

Baseline Week 14

Drucker et al, Lancet (2008)

0 0

AUC (µg min/mL)

Effect of liraglutide on paracetamol absorption (AUC 0-1h) in type 2 diabetes (n=18)

Flint et al, Adv Ther (2011)

1 week 2 weeks 3 weeks 0.6mg 1.2mg 1.8mg

* *

µg min/mL

Effect of lixisenatide (~20µg) on gastric emptying in type 2 diabetes

Lixisenatide QD (n=17) Placebo (n=17)

Change in gastric emptying from baseline to Day 28

lag

(min

)

Lixisenatide BID (n=14)

-50

0

50

100

150

200

-100

-50

0

50

100

150

200

250

300

T50

(min

)

Lorenz et al, Regul Pept (2013)

Relationship between the effect of lixisenatide (20 µg QD) on blood glucose at day 28 with the change in

gastric emptying from baseline in type 2 diabetes (n=17)

Lorenz et al, Regul Pept (2013)

r= 0.71, P<0.05

Δ in gastric emptying T50 (h) 1 2 3 4 5

AU

C g

luco

se (m

g*h/

dl)

Comparative effects of lixisenatide (20µg) and liraglutide (1.8 mg) on postprandial glucose and

insulin in type 2 patients on metformin at 4 weeks

Glu

cose

(mg/

dl)

Day-1 Day-28

Meal 451 kcal

45 -30

0

30

60

270 210 180 120 90 60

90 P<0.0001

Kapitza et al, Diabetes Obes Metab (2013)

Insu

lin fr

ee (µ

IU/m

l)

0 0

40

60

70

270 210 90 30

50

30

20

60 150

Meal 451 kcal

Day-1 Day-28

Glucose* Insulin

P<0.0001

lixisenatide liraglutide

* 1° study endpoint,

•  insulin therapy primarily targets pre-prandial glucose and causes hypoglycaemia and weight gain •  some GLP-1 receptor agonists predominantly target

post-prandial glycaemia and their use is associated with a low risk of hypoglycaemia and weight loss •  combined use of basal insulin with a GLP-1 agonist

may optimise glycaemic control with a lower risk of hypoglycaemia and weight gain

Combination of basal insulin and GLP-1 agonist in type 2 diabetes

Mea

n H

bA1c

(%)

Week Week 24 LOCF

8.6

8.4

8.2

8.0

7.8

7.6

7.4

7.2 0 4 8 12 16 20 24

8.1%

7.8%

Basal insulin ± MET + placebo (n = 158) Basal insulin ± MET + lixisenatide (n = 304)

Use of once daily lixisenatide in basal insulin treated patients with type 2 diabetes -

changes in HbA1c after 24 weeks - GetGoal-L

Riddle et al, Diabetes Care (2013)

P < 0.001

0

5

10

15

20

25

30

35

Comparative effects of lixisenatide and rapid-acting insulin as add-on to basal insulin in type 2 diabetes –

% of patients achieving HbA1c<7.0%, no weight gain and no symptomatic hypoglycaemia

Raccah et al, J Diabetes Complications

(2014) Basal + LIXI

(n=144) Basal + RAI

(n=144)

P<0.05 OR: 1.90; 95% CI: 1.01, 3.55

(%)

Meta-analysis of 5 randomised controlled trials

•  GLP-1 agonists may slow gastric emptying markedly – the magnitude of this effect is dependent on the ‘baseline’ rate of gastric emptying

•  the reduction in postprandial glycaemia and impact on postprandial insulin induced by GLP-1 agonists are related to the magnitude of slowing of gastric emptying

•  the slowing of gastric emptying induced by liraglutide and exenatide LAR (and presumably other ‘long-acting’ GLP-1 agonists), but not exenatide and lixisenatide (‘short-acting’) diminishes markedly with time, reflecting the pharmacokinetic profile of GLP-1 receptor activation

•  ‘baseline’ gastric emptying and the priority for reducing postprandial glucose excursions are likely to be relevant to the choice of GLP-1 agonist in type 2 patients; ‘prandial’ drugs may be optimally combined with basal insulin